tbuckley/cabot-search huggingface dataset:
C-reactive protein impairs immune response of CD8<sup>+</sup>T cells via FcγRIIb-p38MAPK-ROS axis in multiple myeloma
Authors: Jinxing Jiang, Ziyi Peng, Junying Wang, Mengping Chen, Yike Wan, Honghui Huang, Zhiqiang Liu, Jingya Wang, Jian Hou
Journal: Journal for ImmunoTherapy of Cancer (2023)

Background C-reactive protein (CRP) is a prototypical acute phase protein in humans with the function of regulating immune cells. Serum CRP levels are elevated in multiple myeloma (MM), associated with MM cell proliferation and bone destruction. However, its direct effects on T lymphocytes in MM have not been elucidated. Methods Public data sets were used to explore the correlation of CRP levels with immune cell infiltration and cytotoxicity score of CD8 + T cells in MM. In vitro, repeated freeze-thaw myeloma cell lines were taken as tumor antigens to load dendritic cells (DCs) derived from HLA-A*0201-positive healthy donors. MM-specific cytotoxic T cells (MM-CTL) were obtained from T lymphocytes of the corresponding donors pulsed with these DCs. B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T cells were manipulated by transfecting with lentivirus encoding an anti-BCMA single-chain variable fragment. Then T cells from healthy controls, MM-CTLs and BCMA CAR-T cells were exposed to CRP and analyzed for cell proliferation, cytotoxicity, immunophenotypes. CRP binding capacity to T cells before and after Fc gamma receptors IIb (FcγRIIb) blockage, p38 mitogen-activated protein kinase (MAPK) pathway and the downstream molecules were also detected. In vivo, both normal C57BL/6J mice and the Vk*MYC myeloma mouse models were applied to confirm the impact of CRP on T cells. Results CRP levels were negatively correlated with cell-infiltration and cytotoxicity score of CD8 + T cells in MM. In vitro experiments showed that CRP inhibited T-cell proliferation in a dose-dependent manner, impaired the cytotoxic activity and upregulated expression of senescent markers in CD8 + T cells. In vivo results validated the suppressive role of CRP in CD8 + T cells. CRP could bind to CD8 + T cells, mainly to the naïve T subset, while the binding was dramatically decreased by FcγRIIb blockage. Furthermore, CRP resulted in increased phosphorylation of p38 MAPK, elevated levels of reactive oxygen species and oxidized glutathione in CD8 + T cells. Conclusions We found that CRP impaired immune response of CD8 + T cells via FcγRIIb-p38MAPK-ROS signaling pathway. The study casted new insights into the role of CRP in anti-myeloma immunity, providing implications for future immunotherapy in MM.
Psychosocial Factors of Women Presenting With Myocardial Infarction With or Without Obstructive Coronary Arteries
Authors: Anaïs Hausvater, Tanya M. Spruill, Yuhe Xia, Nathaniel R. Smilowitz, Milla Arabadjian, Binita Shah, Ki Park, Caitlin Giesler, Kevin Marzo, Dwithiya Thomas, Janet Wei, Jeffrey Trost, Puja K. Mehta, Bryan Har, Kevin R. Bainey, Hua Zhong, Judith S. Hochman, Harmony R. Reynolds
Journal: Journal of the American College of Cardiology (2023)
A clinical review of structural damage in psoriatic arthritis for dermatologists: From pathogenesis to ongoing controversies
Authors: Joseph F. Merola, Soumya D. Chakravarty, Olivia Choi, Daphne Chan, Alice B. Gottlieb
Journal: Journal of the American Academy of Dermatology (2023)

Psoriatic arthritis (PsA) is a chronic inflammatory disease that often goes unrecognized in patients with psoriasis. As a result, patients may develop significant structural damage before diagnosis and initiation of adequate treatment. Dermatologists are in an unique position to identify early signs and symptoms of PsA. Here, we briefly review the pathogenesis of PsA, differences in PsA presentation within real-world dermatology practice versus rheumatology clinical trials, and imaging modalities that can be used to assess structural damage. We then discuss several ongoing controversies related to prediction, assessment, and treatment of PsA-related structural damage. Debated questions include the following: (1) Does subclinical enthesitis predict progression from psoriasis to PsA?, (2) Does methotrexate inhibit progression of structural damage?, (3) Does structural damage correlate with clinical disease activity?, and (4) Can progression from psoriasis to PsA be prevented? Evidence presented herein suggests that dermatologists, together with rheumatologists, can play important roles in the early diagnosis and treatment of PsA, thereby potentially preventing irreversible structural damage.
Impact of Positron Emission Tomographic Myocardial Perfusion Imaging on Patient Selection for Revascularization
Authors: Krishna K. Patel, A. Iain McGhie, Kevin F. Kennedy, Randall C. Thompson, John A. Spertus, Brett W. Sperry, Leslee J. Shaw, Timothy M. Bateman
Journal: Journal of the American College of Cardiology (2023)
Teprotumumab-Related Adverse Events in Thyroid Eye Disease
Authors: Shreya A. Shah, Linus Amarikwa, Connie M. Sears, Kevin D. Clauss, Raneem D. Rajjoub, Julia Y. Kang, Madhura A. Tamhankar, César A. Briceño, Andrew R. Harrison, Chrysoula Dosiou, Kimberly P. Cockerham, Sara T. Wester, Raymond S. Douglas, Andrea L. Kossler
Journal: Ophthalmology (2023)
Metixene is an incomplete autophagy inducer in preclinical models of metastatic cancer and brain metastases
Authors: Jawad Fares, Edgar Petrosyan, Deepak Kanojia, Crismita Dmello, Alex Cordero, Joseph T. Duffy, Ragini Yeeravalli, Mayurbhai H. Sahani, Peng Zhang, Aida Rashidi, Victor A. Arrieta, Ilya Ulasov, Atique U. Ahmed, Jason Miska, Irina V. Balyasnikova, C. David James, Adam M. Sonabend, Amy B. Heimberger, Maciej S. Lesniak
Journal: Journal of Clinical Investigation (2023)

A paucity of chemotherapeutic options for metastatic brain cancer limits patient survival and portends poor clinical outcomes. Using a CNS small-molecule inhibitor library of 320 agents known to be blood-brain barrier permeable and approved by the FDA, we interrogated breast cancer brain metastasis vulnerabilities to identify an effective agent. Metixene, an antiparkinsonian drug, was identified as a top therapeutic agent that was capable of decreasing cellular viability and inducing cell death across different metastatic breast cancer subtypes. This agent significantly reduced mammary tumor size in orthotopic xenograft assays and improved survival in an intracardiac model of multiorgan site metastases. Metixene further extended survival in mice bearing intracranial xenografts and in an intracarotid mouse model of multiple brain metastases. Functional analysis revealed that metixene induced incomplete autophagy through N-Myc downstream regulated 1 (NDRG1) phosphorylation, thereby leading to caspase-mediated apoptosis in both primary and brain-metastatic cells, regardless of cancer subtype or origin. CRISPR/Cas9 KO of NDRG1 led to autophagy completion and reversal of the metixene apoptotic effect. Metixene is a promising therapeutic agent against metastatic brain cancer, with minimal reported side effects in humans, which merits consideration for clinical translation.
IPMNs of the Pancreas: More Epidemiologically Than Clinically Relevant
Authors: Stefano Crippa, Gabriele Capurso, Massimo Falconi
Journal: JAMA Network Open (2023)

Jaime de la Fuente, MD; Arjun Chatterjee, MBBS; Jacob Lui, MD; Avinash K. Nehra, MD; Matthew G. Bell, MD; Ryan J. Lennon, MS; Blake A. Kassmeyer, MS; Rondell P. Graham, MBBS; Hiroki Nagayama, MD, PhD; Phillip J. Schulte, PhD; Karen A. Doering, MBA, CCRP; Adriana M. Delgado, MA; Santhi Swaroop Vege, MD; Suresh T. Chari, MD; Naoki Takahashi, MD; Shounak Majumder, MD
2022 American College of Rheumatology Guideline for the Prevention and Treatment of <scp>Glucocorticoid‐Induced</scp> Osteoporosis
Authors: Mary Beth Humphrey, Linda Russell, Maria I. Danila, Howard A. Fink, Gordon Guyatt, Michael Cannon, Liron Caplan, Sara Gore, Jennifer Grossman, Karen E. Hansen, Nancy E. Lane, Nina S. Ma, Marina Magrey, Tim McAlindon, Angela Byun Robinson, Sumona Saha, Charles Womack, Basma Abdulhadi, Julia F. Charles, Jonathan T. L. Cheah, Sharon Chou, Itivrita Goyal, Katherine Haseltine, Lesley Jackson, Reza Mirza, Iram Moledina, Emma Punni, Tim Rinden, Marat Turgunbaev, Katherine Wysham, Amy S. Turner, Stacey Uhl
Journal: Arthritis & Rheumatology (2023)

Objective The objective is to update recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving &gt;3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. Methods An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. Results For adults beginning or continuing &gt;3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x‐ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision‐making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high‐dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. Conclusion This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.
Adult Attention-Deficit/Hyperactivity Disorder and the Risk of Dementia
Authors: Stephen Z. Levine, Anat Rotstein, Arad Kodesh, Sven Sandin, Brian K. Lee, Galit Weinstein, Michal Schnaider Beeri, Abraham Reichenberg
Journal: JAMA Network Open (2023)

Importance Evidence that adult attention-deficit/hyperactivity disorder (ADHD) is associated with an increased risk of dementia is scarce and inconsistent, and potential sources of bias are untested. Objective To examine the association between adult ADHD and the risk of dementia. Design, Setting, and Participants This prospective national cohort study consisted of 109 218 members of a nonprofit Israeli health maintenance organization born between 1933 and 1952 who entered the cohort on January 1, 2003, without an ADHD or dementia diagnosis and were followed up to February 28, 2020. Participants were aged 51 to 70 years in 2003. Statistical analysis was conducted from December 2022 to August 2023. Exposure Adult ADHD was a time-varying covariate, classified as present from the age of the first diagnosis (using the International Classification of Diseases, Ninth Revision , and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision ); otherwise, absent. Main Outcome and Measures Cox regression models were fitted to quantify the association between adult ADHD and the risk of incident dementia with hazard ratios (HRs) and their 95% CIs unadjusted and in the primary analysis, using inverse probability weights, adjusted for 18 sources of potential confounding. In 14 complementary analyses, subgroup and sensitivity analyses were implemented. Results At the beginning of the follow-up, the sample of 109 218 participants had a mean (SD) age of 57.7 (5.5) years, 56 474 participants (51.7%) were female, and 52 744 (48.3%) were male. During follow-up, 730 participants (0.7%) received a diagnosis of adult ADHD, and 7726 (7.1%) received a diagnosis of dementia. Dementia occurred among 96 of 730 participants (13.2%) with adult ADHD and 7630 of 108 488 participants (7.0%) without adult ADHD. In the primary analysis, compared with the absence of adult ADHD, the presence of adult ADHD was statistically significantly ( P &amp;amp;lt; .001) associated with an increased dementia risk (unadjusted HR, 3.62 [95% CI, 2.92-4.49; P &amp;amp;lt; .001]; adjusted HR, 2.77 [95% CI, 2.11-3.63; P &amp;amp;lt; .001]). Twelve of the 14 complementary analyses did not attenuate the conclusions based on the results of the primary analysis. There was, however, no clear increase in the risk of dementia associated with adult ADHD among those who received psychostimulant medication, and evidence of reverse causation was mild. Conclusions and Relevance In this cohort study of individuals born between 1933 and 1952 and followed up in old age, adult ADHD was associated with an increased risk of dementia. Policy makers, caregivers, patients, and clinicians may wish to monitor reliably for ADHD in old age.
Postacute Sequelae of SARS-CoV-2 Infection—Reply
Authors: Tanayott Thaweethai, Andrea S. Foulkes
Journal: JAMA (2023)

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Nrg1 Regulates Cardiomyocyte Migration and Cell Cycle in Ventricular Development
Authors: Joaquim Grego-Bessa, Paula Gómez-Apiñaniz, Belén Prados, Manuel José Gómez, Donal MacGrogan, José Luis de la Pompa
Journal: Circulation Research (2023)

Cardiac ventricles provide the contractile force of the beating heart throughout life. How the primitive endocardium-layered myocardial projections called trabeculae form and mature into the adult ventricles is of great interest for biology and regenerative medicine. Trabeculation is dependent on the signaling protein Nrg1 (neuregulin-1). However, the mechanism of action of Nrg1 and its role in ventricular wall maturation are poorly understood.
Race and Ethnicity and Prehospital Use of Opioid or Ketamine Analgesia in Acute Traumatic Injury
Authors: Dalton C. Brunson, Kate A. Miller, Loretta W. Matheson, Eli Carrillo
Journal: JAMA Network Open (2023)

Importance Racial and ethnic disparities in pain management have been characterized in many hospital-based settings. Painful traumatic injuries are a common reason for 911 activations of the EMS (emergency medical services) system. Objective To evaluate whether, among patients treated by EMS with traumatic injuries, race and ethnicity are associated with either disparate recording of pain scores or disparate administration of analgesia when a high pain score is recorded. Design, Settings, and Participants This cohort study included interactions from 2019 to 2021 for US patients ages 14 to 99 years who had experienced painful acute traumatic injuries and were treated and transported by an advanced life support unit following the activation of the 911 EMS system. The data were analyzed in January 2023. Exposures Acute painful traumatic injuries including burns. Main Outcomes and Measures Outcomes were the recording of a pain score and the administration of a nonoral opioid or ketamine. Results The study cohort included 4 781 396 EMS activations for acute traumatic injury, with a median (IQR) patient age of 59 (35-78) years (2 497 053 female [52.2%]; 31 266 American Indian or Alaskan Native [0.7%]; 59 713 Asian [1.2%]; 742 931 Black [15.5%], 411 934 Hispanic or Latino [8.6%], 10 747 Native Hawaiian or other Pacific Islander [0.2%]; 2 764 499 White [57.8%]; 16 161 multiple races [0.3%]). The analysis showed that race and ethnicity was associated with the likelihood of having a pain score recorded. Compared with White patients, American Indian and Alaskan Native patients had the lowest adjusted odds ratio (AOR) of having a pain score recorded (AOR, 0.74; 95% CI, 0.71-0.76). Among patients for whom a high pain score was recorded (between 7 and 10 out of 10), Black patients were about half as likely to receive opioid or ketamine analgesia as White patients (AOR, 0.53; 95% CI, 0.52-0.54) despite having a pain score recorded almost as frequently as White patients. Conclusions and Relevance In this nationwide study of patients treated by EMS for acute traumatic injuries, patients from racial or ethnic minority groups were less likely to have a pain score recorded, with Native American and Alaskan Natives the least likely to have a pain score recorded. Among patients with a high pain score, patients from racial and ethnic minority groups were also significantly less likely to receive opioid or ketamine analgesia treatment, with Black patients having the lowest adjusted odds of receiving these treatments.
Do autologous platelet concentrates (<scp>APCs</scp>) have a role in intra‐oral bone regeneration? A critical review of clinical guidelines on decision‐making process
Authors: Marc Quirynen, Sam Siawasch, Andy Temmerman, Simone Cortellini, Rutger Dhondt, Wim Teughels, Anna B. Castro
Journal: Periodontology 2000 (2023)

Abstract In the past decades, personalized regenerative medicine has gained increased attention. Autologous platelet concentrates (APCs) such as PRP, PRGF, and L‐PRF, all serving as a source of a large variety of cells and growth factors that participate in hard and soft tissue healing and regeneration, could play a significant role in regenerative periodontal procedures. This narrative review evaluated the relative impact of APCs in alveolar ridge preservation, sinus floor augmentation, and the regeneration of bony craters around teeth, both as a single substitute or in combination with a xenograft. L‐PRF has a significant beneficial effect on alveolar ridge preservation (&lt;alveolar bone resorption, &gt;bone quality). The data for PRGF are less convincing, and PRP is controversial. L‐PRF can successfully be used as a single substitute during transcrestal (≥3.5 mm bone gain) as well as 1‐stage lateral window sinus floor elevation (&gt;5 mm bone gain). For PRGF and especially PRP the data are very scarce. In the treatment of bony craters around teeth, during open flap debridement, L‐PRF as a single substitute showed significant adjunctive benefits (e.g., &gt;PPD reduction, &gt;CAL gain, &gt;crater depth reduction). The data for PRP and PRGF were non‐conclusive. Adding PRP or L‐PRF to a xenograft during OFD resulted in additional improvements (&gt;PPD reduction, &gt;CAL gain, &gt;bone fill), for PRGF no data were found. Autologous platelet concentrates demonstrated to enhance bone and soft tissue healing in periodontal regenerative procedures. The data for L‐PRF were most convincing. L‐PRF also has the advantage of a greater simplicity of production, and its 100% autologous character.
Platelet Membrane‐Enclosed Bioorthogonal Catalysis for Combating Dental Caries
Authors: Mamata Karmacharya, Sumit Kumar, Yoon Jeong Choi, Yoon‐Kyoung Cho
Journal: Advanced Healthcare Materials (2023)

Platelets have shown promise as a means to combat bacterial infections, fostering the development of innovative therapeutic approaches. However, several challenges persist, including cargo loading issues, limited efficacy against biofilms, and concerns regarding the impact of payloads on the platelet carriers. Here, human platelet membrane vesicles (h-PMVs) encapsulating supramolecular metal catalysts (SMCs) as "nanofactories" to convert prodrugs into antimicrobial compounds within close proximity to bacteria are introduced. Having established the feasibility and effectiveness of the SMCs within h-PMVs, referred to as the PLT-reactor, to activate pro-antibiotic drugs (pro-ciprofloxacin and pro-moxifloxacin) using model organisms (Escherichia coli ATCC 25922 and Staphylococcus aureus ATCC 25923), the investigation is subsequently extended to oral biofilms, with a particular emphasis on Streptococcus mutans 3065. This "bind and kill" strategy demonstrates the potent antimicrobial specificity of the PLT-reactor through localized antibiotic production. h-PMVs play a pivotal role by enabling precise targeting of pathogenic biofilms on natural teeth while minimizing potential hemolytic effects. The finding indicates that platelet membrane-cloaked surfaces exhibit robust, multifaceted, and pathogen-specific binding affinity with excellent biocompatibility, making them a promising alternative to antibody-based therapies for infectious diseases.
Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma
Authors: Malcolm F McDonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang
Journal: Neuro-Oncology (2023)

Abstract Background Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs. Methods We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function. Results Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail. Conclusion eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.